1. Technical Field
The present invention generally relates to an improved process for the preparation of perindopril and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to a process which forms a novel intermediate in the preparation of perindopril erbumine.
2. Description of the Related Art
Perindopril erbumine, also known as (2S,3aS,7aS)-1-[(S)-N-[(S)-1-carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1), is represented by the structure of Formula I.
The tert-butylamine salt of perindopril, also known as perindopril erbumine, is the form commercially sold under the trade name Aceon®. Perindopril is the free acid form of perindopril erbumine and is an ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril is also a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite. Perindopril is ordinarily used to treat hypertension.
It is believed that perindopril lowers blood pressure primarily through inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.
U.S. Pat. No. 4,914,214 (“the '214 patent”), incorporated by reference herein, discloses a process for the preparation of perindopril. A process disclosed in the '214 patent for the preparation of perindopril involves hydrogenating indoline-2-carboxylic acid (1) in methanol over a rhodium-aluminum oxide (Rh/Al2O3) catalyst to form (2S,3aS,7aS)-octahydroindole-2-carboxylic acid of the formula (2). The acid of formula (2) is then esterified with thionyl chloride and benzyl alcohol to yield (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester (3), which is one key intermediate of perindopril. Another key intermediate of perindopril is prepared by reacting L-norvaline (4) with thionyl chloride and ethanol to form an ethyl ester (5). The ethyl ester (5) is reacted with sodium pyruvate (6) and subjected to hydrogenation to form N-1S-carboxyethylbutyl-(S)-alanine (7), another key intermediate. (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester (3) is then coupled with N-1S-carboxyethylbutyl-(S)-alanine (7) in presence of sodium dicyclohexyl dicarbodiimide (DCC) to yield perindopril benzylated ester (8). Perindopril benzylated ester (8) is hydrolyzed to form perindopril (9). Perindopril (9) is reacted with tert-butylamine to form the perindopril erbumine salt (I) as generally shown below in Scheme I.

WO 2004/075889, incorporated by reference herein, also discloses a process for preparing perindopril which includes reacting the benzyl ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole with N-[(S)-1-carbethoxybutyl]-(S)-alanyl chloride or bromide in the presence of a suitable base followed by debenzylation by catalytic hydrogenation. However, this method is relatively time consuming and not cost effective because the debenzylation uses a Pd/C catalyst.
Several drawbacks are further associated with the processes of the prior art. For example, several drawbacks include the use of toxic reagents with stringent standards, expensive reagents that are not easily recycled, and numerous steps that add to process inefficiencies and complications during commercial production.
Accordingly, there remains a need for improved processes for preparing perindopril that eliminate and reduce the drawbacks of the prior art in a convenient and cost efficient manner on a commercial scale.